ASYMMETRIC TOTAL SYNTHESIS OF DIBENZOCYCLOOCTADIENE LIGNANS (-)-SCHIZANDRIN AND (-)-ISOSCHIZANDRIN - STRUCTURE REVISION OF (+)-ISOSCHIZANDRIN

The oxazoline-mediated biaryl coupling reaction was applied successfully to the total synthesis of a series of dibenzocyclooctadiene lignans in chiral nonracemic form. The diastereoselectivities achieved in the coupling reaction varied in a predictable manner, primarily as a function of the ortho substituents on the phenyl Grignard reagent. Chiral cyclooctanones 17r and 17s were accessible in 23% overall yield (seven isolated intermediates) from the preparatively useful biaryl coupling of phenyl bromide 5c with phenyloxazoline 6. For both ketones, nucleophilic attack occurred preferentially trans to the C-8 methyl substituent. Methyllithium addition to 17s gave a single product (18). The epimeric alcohol 21 was prepared selectively (10:1) by an olefination-epoxidation-reduction sequence. Methyllithium addition to 17r gave an 8:1 mixture of (-)-isoschizandrin (22) and (-)-schizandrin (23). Chemical and spectroscopic evidence supported the reassignment of the structure for natural (+)-isoschizandrin to the 15,16R,7R,8S configuration. © 1990, American Chemical Society. All rights reserved.